Sex hormones
Dr. Entisar Al-Mukhtar
Androgens
• Have anabolic and/or masculinizing effects in both males & females.
• Testosterone, the most important androgen synthesized by Leydig cells in the
testes & in smaller amounts, by thecal cells in the ovary & by the adrenal gland in
both sexes.
• Testes secreted other androgens including 5α-dihydrotestosterone (DHT),
androstenedione & dehydroepiandrosterone (DHEA) in small amounts. In males,
testosterone secretion is controlled by GnRH, which stimulate FSH & LH
secretion from anterior pituitary. [Note: LH stimulates steroidogenesis in the
Leydig cells, whereas FSH is necessary for spermatogenesis.]
Testosterone or its active metabolite DHT inhibits production of FSH & LH through
a negative feedback loop and thus, regulates testosterone production.
The androgens are necessary for:
1. Normal maturation in the male
2. Sperm production.
3. Increased synthesis of muscle proteins & Hb.
4. Decreased bone resorption.
Synthetic modifications of the androgen are designed to (1) modify solubility and
susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone),
and (2) separate anabolic and androgenic effects.
Mechanism of action:
Testosterone itself is the active ligand in muscle and liver,but in other tissues it must
be metabolized to derivatives such as DHT. For example, after diffusing into the cells
of the prostate, seminal vesicles, epididymis and skin, testosterone is converted by
5α-reductase to DHT.
Therapeutic uses
1. Androgenic steroid: indicated for primary hypogonadism (due to Leydig cell
dysfunction) or, secondary hypogonadism (due to hypothalamic or pituitary
failure) .
2. Anabolic steroids: used to treat chronic wasting associated with HIV or cancer.
They may also be used as adjunct therapy in severe burns & to speed recovery from
surgery or chronic debilitating disease.
Note: Unapproved use of anabolic steroids is to increase lean body mass, muscle
strength and endurance in athletes & body builder. In some popular publications,
1
DHEA (testosterone & estrogen precursor) has been touted as the antiaging
hormone as well as a "performance enhancer". With its ready availability in health
food stores, the drug has been abused. There is no definitive evidence that it slows
aging, or that it improves performance at normal therapeutic doses.
3. Endometriosis: Danazol (a mild androgen), is used for the treatment of
endometriosis (ectopic growth of endometrium) & fibrocystic breast disease.
It inhibits release of FSH & LH but has no effect on the aromatase.
Weight gain, acne, decreased breast size, deepening voice, increased libido &
increased hair growth are among the adverse effects.
Pharmacokinetics
1. Testosterone:
• Ineffective orally (first-pass metabolism).
• C17-esters of testosterone (eg. testosterone cypionate or enanthate) are
administered I.M.
Note: addition of esters increase hormone lipid solubility & duration of action.
• Transdermal patches, topical gels & buccal tablets of testosterone are also
available.
• Testosterone & its esters exhibit a 1:1 relative ratio of androgenic to anabolic
activity.
2. Testosterone derivatives:
• Alkylation of testosterone allows its oral administration (e.g., fluoxymesterone )
• Fluoxymesterone is an orally effective agent with long half-life & it has a 1:2
androgenic to anabolic ratio.
• Oxandrolone is an orally active testosterone derivative with anabolic activity 3 to
13 times that of testosterone.
• Hepatic adverse effects are associated with 17 α -alkylated androgens.
Adverse effects
1. In females:
• Masculinization, acne, growth of facial hair, deep voice, male pattern baldness &
excessive muscle development. Menstrual irregularities may also occur.
• Testosterone should not be used by pregnant women (virilization of female fetus
may occur).
2. In males:
• Priapism, impotence, decreased spermatogenesis & gynecomastia.
• Cosmetic changes like those described for females may occur.
• Stimulate of prostate growth.
2
3. In children:
• Abnormal sexual maturation & growth disturbances due to premature closure of
the epiphyseal plates.
4. General effects:
• Increase LDL & decrease HDL levels thus, LDL:HDL ratio & risk of premature
CHD are increased.
• Fluid retention & edema.
5. In athletes:
• Anabolic steroids, (eg, DHEA) used by athletes can cause premature closing of
the long bones epiphysis, which stunts growth & interrupts development.
• High doses taken by young athletes may result in (1) reduction of testicular size,
(2) hepatic abnormalities, (3) increased aggression (“roid rage”), (4) major mood
disorders & (5) other adverse effects described above.
Antiandrogens
• They either inhibit androgens synthesis or by blocking their receptors.
• Finasteride and dutasteride, are used for the treatment of BPH, they inhibit 5αreductase decreasing DHT formation in the prostate & reducing its size.
• Flutamide, bicalutamide, enzalutamide and nilutamide act as competitive
inhibitors of androgens & are effective orally for the treatment of prostatic cancer.
• Cyproterone is a progesterone derivative, it competes on testosterone receptors in
peripheral organs reducing spermatogenesis that may even cause azoospermia
(reversible over 4 months after drug discontinuation), it also compete on
testosterone receptors in the CNS reducing sexual drive & thoughts resulting in
impotence.
• Due to its progesterone activity, cyproterone inhibits gonadotrophin secretion
decreasing testicular androgen production.
Cyproterone uses:
1. Reduce male hypersexuality.
2. Prostatic CA.
3. Cyproterone-ethinylestradiol combination (Dianette) is used to treat severe
hirsutism & acne in female. This combination is also used as an OC (but should
not be used primarily for this purpose).
• Spironolactone competes on DHT receptors, it is used to treat hirsutism in
female.
3